1. Field of the Invention
The invention relates to a method of preventing or treating human immunodeficiency virus (“HIV”) and simian-human immunodeficiency virus (“SHIV”) by using antisense (“AS”) nucleic acids of interleukin-4 (“IL-4”).
2. Description of Related Art
HIV induces a persistent and progressive infection leading, in the vast majority of cases, to the development of the acquired immunodeficiency syndrome (“AIDS”). There are at least two distinct types of HIV: HIV-1 and HIV-2. HIV infection leads to immune incompetence, opportunistic infections, neurological dysfunctions, neoplastic growth, and ultimately death.
HIV uses a receptor-mediated pathway in the infection of host cells. HIV requires contact with two cell-surface receptors to gain entry into cells and initiate infection; CD4 is the primary receptor. CXCR4 (“X4”) and CCR5 (“R5”), members of the chemokine receptor family of proteins, serve as secondary co-receptors for HIV isolates that have historically been called tropic for T cell lines or macrophages, respectively. CXCR4 or CCR5, in conjunction with CD4, form a functional cellular receptor for entry of certain strains of HIV into cells.
One analogous model system for HIV infection is the SHIV system. See generally Narayan, U.S. Pat. No. 5,849,994, which is incorporated by reference. The pathogenesis of SHIV in non-human primates is also underpinned by the productive infection of CD4+ T cells and macrophages. In the macaque model, pathogenic X4 SHIV includes SHIVKU-2 (Raghavan 1997) and the dual tropic SHIV89.6P (Reinmann 1996, Doranz 1996) are often used to investigate pathenogenesis.
Some studies on the impact of various cytokines in HIV and SHIV have been performed. For example, studies on replication of X4 HIV-1 in human macrophage cultures showed that IL-4 caused significant enhancement of virus replication (Valentin 1998). It was also shown opportunistic pathogens that induce IL-4 could promote replication of the virus in tissue macrophages of SHIV-infected macaques. In that study, Schistosoma mansoni eggs, potent inducers of Th-2 cytokines, were injected into the portal vein or intratracheally into SHIV-infected macaques. This resulted in the development of granulomas in the liver and lung in a milieu rich in IL-4. Macrophages comprising the granulomas were shown to be productively infected with the virus. In the same study, it was shown that macrophages in Freund's adjuvant-induced granulomas that were rich in interferon (“IFN”)-gamma were poorly permissive for virus replication (Buch 2001). While the use of IL-4 antagonists to treat HIV has been theorized, no anti-viral therapeutic studies have been performed either in vitro or in vivo. See generally Furfine, U.S. Published Patent Application No. 2003/0211104.
The present invention is directed to a novel approach for treating HIV and SHIV viral infection. In the present invention, AS IL-4 was successfully used to inhibit replication of pathogenic SHIV in cultures of macaque CD4+ T cells and macrophages, and importantly, in macaques infected with the SHIV virus. Further, the present invention showed that the peripheral blood of treated animals had larger number of CD8+ T cells and a higher degree of expression of CD8+ than controls. Lymph nodes of treated animals were better preserved and had a prominent increase in numbers of activated CD8+ T cells. The therapeutic use of AS IL-4 therefore suggested that this cytokine does cause enhanced SHIV replication by increasing cellular receptors, and simultaneously by suppressing antiviral CD8+ T cell responses.